Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death. Cancer is caused by both external factors (i.e., tobacco, chemicals and radiation) and internal factors (inherited mutations, hormones, immune conditions and mutations that occur from metabolism). These causal factors may act together or in sequence to initiate or promote carcinogenesis. Ten or more years may often pass between exposure to external factors and detectable cancer. Cancer is treated by surgery, radiation, chemotherapy, hormones and immunotherapy.
All cancers involve the malfunction of genes that control cell growth and division. About 5% to 10% of all cancers are clearly hereditary, in that an inherited genetic alteration predisposes the person to a very high risk of particular cancers. The remainder of cancers are not hereditary, but result from damage to genes (mutations) that occur throughout one's lifetime, either due to internal factors, such as hormones or the digestion of nutrients within the cells, or external factors, such as tobacco, chemicals or sunlight.
Lung cancer is the most common cause of cancer death in the world (Jemal et al., CA Cancer J. for Clin. (2005) 55:10-30; Parkin et al., European J. of Cancer (2001) 37:S4-66). In 2005, lung cancer accounted for 13% of the cancer that was diagnosed. The incidence rate has been declining significantly in men, from a high of 102.1 per 100,000 in 1984 to 77.7 in 2001. In women, the rate decreased for the first time from 52.8 in 1998 to 49.1 in 2001, after a long period of increase.
Over 163,000 deaths due to lung cancer were reported in 2005. This accounts for approximately 29% of all cancer deaths. Since 1987, more women have died each year of lung cancer than from breast cancer. Death rates have continued to decline significantly in men since 1991 by about 1.9% per year. Female lung cancer death rates have recently reached a plateau after continuously increasing for several decades. Decreasing lung cancer incidence and mortality rates reflect decreased smoking rates over the past 30 years.
Cigarette smoking is by far the most important risk factor for lung cancer. Other risk factors include second hand smoke and occupational or environmental exposures to substances such as arsenic; some organic chemicals such as benzene; radon and asbestos; radiation exposure from occupational, medical, and environmental sources; air pollution and tuberculosis.
Cancers that begin in the lungs are divided into two major types, non-small cell lung cancer and small cell lung cancer, depending on how the cells look under a microscope. Each type of lung cancer grows and spreads in different ways and is treated differently. Non-small cell lung cancer is more common than small cell lung cancer, and it generally grows and spreads more slowly. There are three main types of non-small cell lung cancer. They are named for the type of cells in which the cancer develops: squamous cell carcinoma, adenocarcinoma and large cell carcinoma.
Squamous cell carcinoma is a cancer that begins in squamous cells, which are thin, flat cells that look like fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Adenocarcinoma is a type of cancer that begins in cells that line certain internal organs and that have glandular (secretory) properties. Still further, large cell carcinoma is a type of cancer in which the cells are large and look abnormal in comparison to the surrounding cells when viewed under a microscope.
Lung cancer can also be classified as to where it is located before the actual type of cancer is identified. For example, lung cancer falls under the disease category of a neoplasm. A neoplasm is an abnormal mass of tissue that results when cells divide more than they should or do not die when they should. The neoplasm can then be further classified as thoracic neoplasms, respiratory tract neoplasms and lung neoplasms depending on where the cells are located. The difference between these locations has to do with definitively locating where the neoplasm exists. For example, a thoracic neoplasm exists in the chest region, a respiratory tract neoplasm includes all of the organs that are involved in breathing (i.e., the nose, throat, larynx, trachea, bronchi, and lungs) and a lung neoplasm is exclusively found in one of a pair of organs in the chest that supplies the body with oxygen, and removes carbon dioxide from the body.
Past efforts at early detection have not yet demonstrated the ability to reduce mortality. Chest x-ray, analysis of cells in sputum, and fiber optic examination of the of the bronchial passages have shown limited effectiveness in improving survival or determining prognosis. Newer tests, such as low-dose spiral computed tomography scans and molecular markers in the sputum, have produced promising results in detecting lung cancers at earlier, more operable stages, when survival is more likely. However, there are considerable risks associated with lung biopsy and surgery which must be considered when evaluating the risks and benefits of screening.
In addition, the current staging system of NSCLC is inadequate to predict outcome, when patients have the same clinical and pathological features. This is evident because approximately 30% of patients that present with NSCLC present with early stage disease and receive potentially curative treatment. However, up to 40% of these patients will relapse within 5 years (Hoffman et al., Lancet (2000) 355:479-485; Mountain, Chest (1997) 111:1710-1717; and Naruke et al., J. Thorac. Cardiovasc. Surg. (1988) 96:440-447).
The introduction of molecular approaches deliver more information for identifying patients at high risk of recurrence or metastasis after resection, which might be improved by the management of NSCLC patients. Gene expression profiling has been shown to be able to classify patients with different survivals as demonstrated by Beer et al. (Beer et al., Nat. Med. (2002) 8:816-824 and Wigle et al., Cancer Res. (2002) 62:3005-3008). In addition, a considerable proportion of clinically early-staged patients were designated through gene expression profile as high-risk for poor prognosis. Nevertheless, clinical application of this gene profiling approach might be still limited by the enormity of the number of genes employed (Ramaswamy, N. Engl. J. Med. (2004) 350:1814-1816). Furthermore, most of genes selected for profiling were substantially heterogeneous across studies for lung cancer, with only very few genes being consistently included (Endoh et al., J. Clin. Oncol. (2004) 22:811-9).
In addition, several recent microarray studies revealed that gene expression profiles can be used to classify the subclasses of histopathological type of lung carcinomas (e.g., adenocarcinoma and SCC). (Bhattacharjee et al., Proc. Natl. Acad. Sci. (2001) 98:13790-13795; Garber et al., Proc. Natl. Acad. Sci. (2001) 98:13784-13789; McDoniels-Silvers et al., Clin. Cancer Res. (2002) 8:1127-1138; McDoniels-Silvers et al., Neoplasia (2002) 4:141-150; and Nacht et al., Proc. Natl. Acad. Sci. (2001) 98:15203-15208). Current data show that the optimal gene expression profile for discriminating subgroups of lung cancer might vary in different populations. For instance, the mutation rate of epidermal growth factor receptor (EGFR) in the populations of East Asian ethnicity (including Taiwan and Japan) have been found to have a higher response rate to treatment than other races (Chou et al., Clin. Cancer Res. (2005) 11:3750-7; Huang et al., Clin. Cancer Res. (2004) 10:8195-8203; Shigematsu et al., J. Natl. Cancer Inst. (2005) 97:339-346).
The inventors of the present invention have previously identified more than 600 genes as being metastasis associated. In the invention to be presented in the following sections, the authors further describe their findings of specific sets of genes which can determine the risk of developing a tumor in a human; identify the subclass of lung cancer, especially distinguishing adenocarcinoma from squamous cell carcinoma; and predict the prognosis of a human with a tumor.